(3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6'-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2'-oxo-1',2'-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3'-indole]-5'-carboxamide p-toluenesulfonate | 1398569-75-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6'-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2'-oxo-1',2'-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3'-indole]-5'-carboxamide p-toluenesulfonate
• 英文别名: (3’R,4’S,5’R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6”-chloro-4’-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2”-oxo-1“,2”-dihydrodispiro[cyclohexane-1,2’-pyrrolidine-3’,3”-indole]-5’-carboxamide p-tolueneulfonate；Milademetan Tosylate
• CAS: 1398569-75-9
• 化学式: C₇H₈O₃S*C₃₀H₃₄Cl₂FN₅O₄
• 分子量: 790.74
• InChiKey: NHIUKVHKLJSJEA-LINJWFRASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  53
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  198
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one 在 ammonium cerium (IV) nitrate 、 三氟化硼乙醚 、 水 、 potassium carbonate 、 1-羟基苯并三唑 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 210.5h， 生成 (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6'-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2'-oxo-1',2'-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3'-indole]-5'-carboxamide p-toluenesulfonate
  参考文献：
  名称：

  Crystals of dispiropyrrolidine derivatives

  摘要：

  提供了一种抑制Mdm2作用的二螺环吡咯啉化合物或其盐的晶体。本发明提供了(3′R,4′S,5′R)—N—[(3R,6S)-6-氨基甲酰四氢-2H-吡喃-3-基]-6″-氯-4′-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2″-酮-1″,2″-二氢二螺[环己烷-1,2′-吡咯啉-3′,3″-吲哚]-5′-羧酰胺或其盐的晶体，该晶体具有抑制Mdm2并具有抗肿瘤活性的特性。本发明还提供了包含该晶体的药物。

  公开号：

  US09359368B2

文献信息

• DISPIROPYRROLIDINE DERIVATIVES
  申请人：Sugimoto Yuuichi

  公开号：US20120264738A1

  公开（公告）日：2012-10-18

  A compound that inhibits interaction between murine double minute 2 (Mdm2) protein and p53 protein and exhibits anti-tumor activity is provided. The present invention provides a dispiropyrrolidine derivative represented by the following formula (1), which has various substituents, inhibits interaction between Mdm2 protein and p53 protein and exhibits anti-tumor activity, wherein R 1 , R 2 , R 3 , ring A, and ring B in formula (1) respectively have the same meanings as defined in the specification.

  提供了一种抑制小鼠双分子2（Mdm2）蛋白与p53蛋白相互作用并具有抗肿瘤活性的化合物。本发明提供了以下式（1）所代表的二螺环吡咯烷衍生物，其具有各种取代基，抑制Mdm2蛋白与p53蛋白之间的相互作用并具有抗肿瘤活性，其中式（1）中的R1、R2、R3、环A和环B分别具有规范中定义的相同含义。
• TREATMENT METHOD COMBINING MDM2 INHIBITOR AND BTK INHIBITOR
  申请人：Daiichi Sankyo Company, Limited

  公开号：EP3284466A1

  公开（公告）日：2018-02-21

  It is intended to provide a medicament and a method for treating cancer comprising a compound having MDM2 inhibiting activity and a compound having BTK inhibiting activity in combination. The present invention provides a medicament comprising (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide or a pharmaceutically acceptable salt thereof and ibrutinib or a pharmaceutically acceptable salt thereof in combination, and a treatment method using these compounds or salts in combination.

  本发明旨在提供一种治疗癌症的药物和方法，其中包括一种具有 MDM2 抑制活性的化合物和一种具有 BTK 抑制活性的化合物。本发明提供了一种药物，包含(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1、2'-吡咯烷-3',3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和伊布替尼或其药学上可接受的盐的组合，以及使用这些化合物或盐组合的治疗方法。
• COMBINATION METHOD FOR TREATING CANCER
  申请人：Daiichi Sankyo Company, Limited

  公开号：EP3260119A1

  公开（公告）日：2017-12-27

  It is intended to provide a medicament and a method for treating cancer comprising a compound having MDM2 inhibiting activity and a compound having FLT3 inhibiting activity in combination. The present invention provides a medicament comprising (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide or a pharmaceutically acceptable salt thereof and N-(5-tert-butyl-isoxazol-3-yl)-N'-4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea or a pharmaceutically acceptable salt thereof in combination, and a treatment method using these compounds or salts in combination.

  本发明旨在提供一种治疗癌症的药物和方法，其中包括一种具有 MDM2 抑制活性的化合物和一种具有 FLT3 抑制活性的化合物。本发明提供了一种药物，其包含(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3'、3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和 N-(5-叔丁基-异恶唑-3-基)-N'-4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐组合，以及使用这些化合物或盐组合的治疗方法。
• COMBINATION THERAPY METHOD USING MDM2 INHIBITOR AND DNA METHYLTRANSFERASE INHIBITOR
  申请人：Daiichi Sankyo Company, Limited

  公开号：EP3527226A1

  公开（公告）日：2019-08-21

  It is intended to provide a medicament and a method for treating cancer, comprising a compound having MDM2 inhibiting activity and a DNA methyltransferase inhibitor in combination. The present invention provides a medicament comprising (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide or a pharmaceutically acceptable salt thereof and a DNA methyltransferase inhibitor in combination, and a treatment method using the compound or a salt thereof and a DNA methyltransferase inhibitor in combination.

  本发明旨在提供一种治疗癌症的药物和方法，包括一种具有 MDM2 抑制活性的化合物和一种 DNA 甲基转移酶抑制剂的组合。本发明提供了一种药物，包含(3'R,4'S,5'R)-N-[(3R,6S)-6-氨基甲酰四氢-2H-吡喃-3-基]-6"-氯-4'-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2"-氧代-1",2"-二氢二螺[环己烷-1,2'-吡咯烷-3'、3"-吲哚]-5'-甲酰胺或其药学上可接受的盐和 DNA 甲基转移酶抑制剂的组合，以及使用该化合物或其盐和 DNA 甲基转移酶抑制剂组合的治疗方法。
• Method for treating cancer by combined use
  申请人：DAIICHI SANKYO COMPANY, LIMITED

  公开号：US10716790B2

  公开（公告）日：2020-07-21

  It is intended to provide a medicament and a method for treating cancer comprising a compound having MDM2 inhibiting activity and a compound having FLT3 inhibiting activity in combination. The present invention provides a medicament comprising (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a pharmaceutically acceptable salt thereof and N-(5-tert-butyl-isoxazol-3-yl)-N′-4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea or a pharmaceutically acceptable salt thereof in combination, and a treatment method using these compounds or salts in combination.

  本发明旨在提供一种治疗癌症的药物和方法，其中包括一种具有 MDM2 抑制活性的化合物和一种具有 FLT3 抑制活性的化合物的组合。本发明提供了一种包含(3′R,4′S,5′R)-N-[(3R、6S)-6-氨基甲酰四氢-2H-吡喃-3-基]-6″-氯-4′-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2″-氧代-1″,2″-二氢二螺[环己烷-1,2′-吡咯烷-3′、3″-吲哚]-5′-甲酰胺或其药学上可接受的盐和N-(5-叔丁基-异恶唑-3-基)-N′-4-[7-(2-吗啉-4-基-乙氧基)咪唑并[2,1-b][1,3]苯并噻唑-2-基]苯基}脲或其药学上可接受的盐组合，以及使用这些化合物或盐组合的治疗方法。